The present invention relates to novel compounds that are A2B adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, A1 adenosine receptor agonists modulate the cardiostimulatory effects of catecholamine, thus slowing the heart rate, and also prolong impulse propagation through the AV node. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and A3 adenosine receptors modulate cell proliferation processes.
Adenosine A2B receptors are ubiquitous, and regulate multiple biological activities. For example, adenosine binds to A2B receptors on endothelial cells, thereby stimulating angiogenesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. Adenosine stimulates A2B receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory activity by ligation with A2B in the intestine. Binding of A2B receptors in the brain leads to the release of IL-6, which provides a protective effect to the cerebrum from ischemia
While many of these biological effects of adenosine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to curtail its effects. For example, the binding of A2B receptors stimulates angiogenesis by promoting the growth of endothelial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia. Accordingly, inhibition of the binding of adensoine to A2B receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation. Adensosine also plays a role in vascular disease by causing the apoptosis of smooth muscle cells, leading to atherosclerosis and restenosis.
A2B receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhus. A2B antagonists can therefore be used to block intestinal chloride secretion, and are thus useful in the treatment of inflammatory gastrointestinal tract disorders, including diarrhea.
Insensitivity to insulin exacerbates diabetes and obesity. Insulin sensivity is decreased by the interaction of adenosine with A2B receptors. Thus, blocking the adenosine A2B receptors of individuals with diabetes or obesity would benefit patients with these disorders.
Another adverse biological effect of adenosine acting at the A2B receptor is the over-stimulation of cerebral IL-6, a cytokine associated with dementias and Altheimer""s disease. Inhibiting the binding of adenosine to A2B to receptors would therefore mitigate those neurological disorders that are produced by IL-6.
Type I hypersensitivtiy disorders, such as asthma, hay fever, and atopic ezcema, are stimulated by binding to A2B-receptors of mast cells. Therefore, blocking these adenosine receptors would provide a therapeutic benefit against such disorders.
There are several compounds presently used in the treatment of asthma. For example, theophylline is an effective antiasthmatic agent, even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, theophylline has substantial side effects, most of which are due to its CNS action, which provide no beneficial effects in asthma, and to the fact that it non-specifically blocks all adenosine receptor subtypes.
Additionally adenosine treatment, such as inhaled adenosine, provokes bronchoconstriction in asthmatics, but not in the normal population. This process is known to involve mast cell activation, in that it releases mast cell mediators, including histamine, PGD2-xcex2-hexosaminidase and tryptase, and because it can be blocked by specific histamine H1 blockers and chromolyn sodium. Accordingly, there is an intrinsic difference in the way adenosine interacts with mast cells from asthmatics, and thus A2B antagonists are particularly useful in modulating mast cell function or in the activation of human lung cells.
Accordingly, it is desired to provide compounds that are potent A2B antagonists, useful in the treatment of various disease states related to modulation of the A2B receptor, in particular cancer, asthma and diarrhea. Preferably, the compounds would be selective for the A2B receptor, thus avoiding side effects caused by interaction with other adenosine receptors.
It is an object of this invention to provide A2B receptor antagonists. Accordingly, in a first aspect, the invention relates to compounds of Formula I: 
wherein:
R1 is optionally substituted alkyl or a group xe2x80x94Yxe2x80x94Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
R2 is hydrogen, acyl, optionally substituted alkyl, or a group xe2x80x94Yxe2x80x94Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
R3 is hydrogen, optionally substituted alkyl or a group xe2x80x94Yxe2x80x94Z1, in which Y is a covalent bond or optionally substituted alkylene, and Z1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when Y is a covalent bond Z cannot be optionally substituted amino;
R4 and R6 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
R5 is hydrogen, optionally substituted alkyl, halo, CF3, nitro, cyano, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amino, optionally substituted sulfoxide, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted acylamino, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
X is oxygen, sulfur, or xe2x80x94NHxe2x80x94;
with the proviso that when Y is a covalent bond and Z or Z1 is alkenyl or alkynyl, the double bond of the alkenyl or the triple bond of the alkynyl is located at least two carbon atoms away from the attachment to the nitrogen.
A second aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient.
A third aspect of this invention relates to a method of using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with an A2B receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, inflammatory gastrointestinal tract disorders, including diarrhea, cardiovascular diseases, such as atherosclerosis, neurological disorders such as senile dementia, Alzheimer""s disease, and Parkinson""s disease, diseases related to unwanted angiogenesis, for example diabetic retinopathy and cancer, and asthma.
One preferred class includes those compounds of Formula I in which X is xe2x80x94NHxe2x80x94, particularly those in which R1 is optionally substituted alkyl and R2 is hydrogen, alkyl or acyl. Of these compounds, more preferred are those in which R1 is optionally substituted alkyl, R2 is hydrogen, and R3 is xe2x80x94Yxe2x80x94Z1, in which Y is optionally substituted alkylene and Z1 is optionally substituted aryl, and R4, R5 and R6 are hydrogen, halogen, optionally substituted alkyl or optionally substituted alkenyl. Even more preferred are those in which R1 is lower alkyl or 1-3 carbon atoms, particularly ethyl or n-propyl, Y is lower alkylene of 1-3 carbon atoms, particularly methylene or ethylene, and Z is optionally substituted phenyl.
Of these preferred compounds, one preferred subclass are those compounds in which R4 and R6 are hydrogen or methyl, and R5 is hydrogen, optionally substituted phenyl, lower alkyl, or lower alkenyl. Particularly preferred are those in which R4, R5 and R6 are all hydrogen.
Definitions and General Parameters
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to:
1) an alkyl group as defined above, having from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
2) an alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and xe2x80x94NRaxe2x80x94, where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term xe2x80x9clower alkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
The term xe2x80x9csubstituted lower alkylxe2x80x9d refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1 to 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1-5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both from 1 to 5 substituents as defined aboveand is also interrupted by 1-5 atoms as defined above.
The term xe2x80x9calkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2-), ethylene (xe2x80x94CH2CH2-), the propylene isomers (e.g., xe2x80x94CH2CH2CH2- and xe2x80x94CH(CH3)CH2-) and the like.
The term xe2x80x9clower alkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 6 carbon atoms.
The term xe2x80x9csubstituted alkylenexe2x80x9d refers to:
(1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
(2) an alkylene group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and NRaxe2x80x94, where Ra is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
(3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of substituted alkylenes are chloromethylene (xe2x80x94CH(Cl)xe2x80x94), amino ethylene (xe2x80x94CH(NH2)CH2xe2x80x94), methylaminoethylene (xe2x80x94CH(NHMe)CH2xe2x80x94), 2-carboxypropylene isomers(xe2x80x94CH2CH(CO2H)CH2xe2x80x94), ethoxyethyl (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94), ethylmethylaminoethyl (xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94OCH2CH2xe2x80x94OCH2CH2xe2x80x94), and the like.
The term xe2x80x9caralkyl: refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. xe2x80x9cOptionally substituted aralkylxe2x80x9d refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x94Oxe2x80x94, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group xe2x80x94Yxe2x80x94Z, in which Y is optionally substituted alkylene and Z is; optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-Oxe2x80x94 and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
The term xe2x80x9calkylthioxe2x80x9d refers to the group Rxe2x80x94Sxe2x80x94, where R is as defined for alkoxy.
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl). Preferred alkenyl groups include ethenyl or vinyl (xe2x80x94CHxe2x95x90CH2), 1-propylene or allyl (xe2x80x94CH2CHxe2x95x90CH2), isopropylene (xe2x80x94C(CH3)xe2x95x90CH2), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.
The term xe2x80x9clower alkenylxe2x80x9d refers to alkenyl as defined above having from 2 to 6 carbon atoms.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9calkynylxe2x80x9d refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (xe2x80x94Cxe2x89xa1CH), propargyl (or propynyl, xe2x80x94CH2Cxe2x89xa1CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9cacylaminoxe2x80x9d refers to the group xe2x80x94NRC (O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9cacyloxyxe2x80x9d refers to the groups xe2x80x94O(O)C-alkyl, xe2x80x94O(O)C-cycloalkyl, xe2x80x94O(O)C-aryl, xe2x80x94O(O)C-heteroaryl, and xe2x80x94O(O)C-heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9carylxe2x80x9d refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2;
The term xe2x80x9caryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term xe2x80x9carylthioxe2x80x9d refers to the group Rxe2x80x94Sxe2x80x94, where R is as defined for aryl.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group xe2x80x94Yxe2x80x94Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9ccarboxyalkylxe2x80x9d refers to the groups xe2x80x94C(O)O-alkyl, xe2x80x94C(O)O-cycloalkyl, where alkyl and cycloalkyl may be optionally substituted as defined herein.
The term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indan, and the like.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluoro, bromo, chloro, and iodo.
The term xe2x80x9cacylxe2x80x9d denotes a group xe2x80x94C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group (i.e., unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole, or benzothienyl). Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogen containing heteroaryl compounds.
The term xe2x80x9cheteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94.
The term xe2x80x9cheterocyclylxe2x80x9d refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and xe2x80x94S(O)nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.
The term xe2x80x9cthiolxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9csubstituted alkylthioxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
The term xe2x80x9cheteroarylthiolxe2x80x9d refers to the group xe2x80x94S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
The term xe2x80x9csulfoxidexe2x80x9d refers to a group xe2x80x94S(O)R, in which R is alkyl, aryl, or heteroaryl. xe2x80x9cSubstituted sulfoxidexe2x80x9d refers to a group xe2x80x94S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term xe2x80x9csulfonexe2x80x9d refers to a group xe2x80x94S(O)2R, in which R is alkyl, aryl, or heteroaryl. xe2x80x9cSubstituted sulfonexe2x80x9d refers to a group xe2x80x94S(O)2R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term xe2x80x9cketoxe2x80x9d refers to a group xe2x80x94C(O)xe2x80x94. The term xe2x80x9cthiocarbonylxe2x80x9d refers to a group xe2x80x94C(S)xe2x80x94. The term xe2x80x9ccarboxyxe2x80x9d refers to a group xe2x80x94C(O)xe2x80x94OH.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
The term xe2x80x9ccompound of Formula Ixe2x80x9d is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
xe2x80x9cIsomersxe2x80x9d are different compounds that have the same molecular formula.
xe2x80x9cStereoisomersxe2x80x9d are isomers that differ only in the way the atoms are arranged in space.
xe2x80x9cEnantiomersxe2x80x9d are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a xe2x80x9cracemicxe2x80x9d mixture. The term xe2x80x9c(xc2x1)xe2x80x9d is used to designate a racemic mixture where appropriate.
xe2x80x9cDiastereoisomersxe2x80x9d are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (xe2x88x92) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical symptoms.
In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
The naming and numbering of the compounds of the invention is illustrated with a representative compound of Formula I in which R1 is ethyl, R2 is hydrogen, R3 is benzyl, R4 and R6 are methyl, R5 is hydrogen, and X is xe2x80x94NHxe2x80x94: 
which is named:
N2-benzyl-8-(3,5-dimethylpyrazol-1-yl)-9-ethyl-9H-purine-2,6-diamine.
Synthetic Reaction Parameters
The terms xe2x80x9csolventxe2x80x9d, xe2x80x9cinert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), dimethylformamide (xe2x80x9cDMFxe2x80x9d), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents.
The term xe2x80x9cq.s.xe2x80x9d means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
The compounds of Formula I may be prepared starting from 2,6-dichloropurine, as shown in Reaction Scheme I. 
where RC(O)-represents R2 when R2 is acyl.
Step 1xe2x80x94Preparation of Formula (2)
The compound of formula (2) is prepared conventionally from the commercially available compound of formula (1), 2,6-dichloropurine, by reaction with an amine of the formula R2NH2. For example, where R2 is hydrogen, ammonia is reacted under pressure in a protic solvent, for example methanol, at a temperature of 60-100xc2x0 C., for about two days. When the reaction is substantially complete, the product of formula (2) is isolated by conventional means, for example removal of the solvent under reduced pressure.
Step 2xe2x80x94Preparation of Formula (3)
The compound of formula (2) is then converted to a compound of formula (3) by alkylation at the 9-position. The compound of formula (2) is reacted with a halide of formula R1X, where R1 is as defined above, with the proviso that it cannot be aryl, and X is chloro, bromo, or iodo, preferably iodo, in the presence of a base, preferably potassium carbonate, in a suitable solvent, preferably acetone. The reaction is preferably conducted at reflux, for about 18 hours. When the reaction is substantially complete, the product of formula (3) is isolated by conventional means, for example removal of the solvent under reduced pressure and slurrying with water before filtering.
Step 3xe2x80x94Preparation of Formula (4)
The 2-chloro moiety is then displaced from the compound of formula (3) by reaction with a compound of formula R3XH when X is NH, in the presence of a base, or R3XM, where X is oxygen or sulfur and M is an alkali metal. The reaction is carried out in an inert protic solvent, preferably n-butanol, at a temperature of about reflux, for about 24-48 hours. When the reaction is substantially complete, the product of formula (4) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Step 4xe2x80x94Preparation of Formula (5)
The compound of formula (4) is then converted to the 8-bromo derivative of formula (5) by reaction with a suitable brominating agent, for example N-bromosuccinimide. The reaction is carried out in an inert solvent, preferably an ether, more preferably tetrahydrofuran, at about room temperature, for about 1-10 hours, preferably about 2 hours. When the reaction is substantially complete, the product of formula (5) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Step 5xe2x80x94Preparation of Formula I where R2 is Hydrogen
The compound of formula (5) is then converted to a compound of Formula I where R2 is hydrogen by reaction with an optionally substituted pyrazole in the presence of an alkali hydride, preferably sodium hydride. The reaction is carried out in an inert polar solvent, preferably dimethylformamide, at about 80xc2x0 C., for about 18 hours. When the reaction is substantially complete, the product of Formula I where R2 is hydrogen is isolated by conventional means, for example by removal of the solvent under reduced pressure, partitioning between dichloromethane and water, separation of the organic layer, removal of solvent, followed by chromatography of the residue on silica gel.
Step 6xe2x80x94Preparation of Formula I where R2 is Acyl
The compound of Formula I where R2 is hydrogen is then converted to a compound of Formula I where R2 is acyl, by reaction with a compound of formula RC(O)Cl, where RC(O)xe2x80x94 represents R2 when R2 is defined as acyl, in the presence of a tertiary base, preferably triethylamine. The reaction is carried out in an inert solvent, preferably toluene, at about reflux temperature for about 18 hours. When the reaction is substantially complete, the product of Formula I where R2 is acyl is isolated by conventional means, for example by partitioning the crude reaction mixture between dichloromethane and water, separating the organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
Preparation of Formula (3) when R1 is Aryl or Heteroaryl
A preferred method of preparing a compound of formula (3) in which R1 is xe2x80x94Yxe2x80x94Z, in which Y is a covalent bond and Z is aryl or heteroaryl is to first react the dichloropurine of formula (1) with a optionally substituted aryl-trialkylstannane in the presence of a copper catalyst, for example copper acetate, and a source of fluoride ions, preferably tetrabutylammonium fluoride. This reaction is described in more detail in Tetrahedron Letters, 43 (2002), 3091-3094, the complete disclosure of which is hereby incorporated by reference.
The product is a 2,6-dichloro-7-arylpurine, which is then reacted as described in step 1 with an amine of formula R2NH2 to give a compound of formula (3) in which R1 is optionally substituted aryl. This reaction is utilized to provide, for example, 2-chloro-6-amino-7-(3-carboxamido)phenyl, a compound of formula (3), which is then converted as shown in Reaction Scheme 1 to a compound of Formula I, for example N2-[2-(3-fluorophenyl)ethylamino)-8-(pyrazol-1-yl)-9-(3-carboxamidophenyl)-9H-purine-2,6-diamine.
An alternative method for preparing compounds of Formula I is shown in Reaction Scheme 2, starting from a compound of formula (5). 
Step 1xe2x80x94Preparation of Formula I where R5 is Iodo
The reaction is carried out as shown in Reaction Scheme 1 above, Step 5, reacting with an optionally substituted 4-iodopyrazole. The compound of Formula I where R5 is iodo is isolated as before.
Step 2xe2x80x94Preparation of Formula I where R5 is Optionally Substituted Phenyl
The compound of Formula I where R5 is iodo is then converted to a compound of Formula I where R5 is optionally substituted phenyl by reaction with an optionally substituted phenylboronic acid. The reaction is carried out in an inert solvent, preferably toluene, in the presence of aqueous sodium carbonate solution and tetrakis(triphenylphosphine)palladium(0), at about reflux temperature for about 24 hours. Excess boronic acid derivative is quenched by addition of hydrogen peroxide. When the reaction is substantially complete, the product of Formula I where R2 is hydrogen is isolated by conventional means, for example by partitioning the crude reaction mixture between dichloromethane and water, separating the organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
Formula I where R5 is Ethyl
Similarly, the compound of Formula I where R5 is iodo is converted to a compound of Formula I where R5 is vinyl by reaction with tributylvinyltin, tetrakis(triphenylphosphine)palladium(0), and copper iodide. This compound is then hydrogenated in the presence of palladium on carbon catalyst. to give a compound of Formula I where R5 is ethyl.
Similarly, reacting the compound of Formula I where R5 is iodo with tri(n-butyl)allyltin, a compound of Formula I where R5 is allyl is produced, which may similarly be reduced to n-propyl.
An alternative method of introducing the pyrazole group to the 8-position of the purine is shown in Reaction Scheme 3. 
Step 1xe2x80x94Preparation of Formula (6)
The compound of formula (5) is converted to a compound of formula (6) by reaction with hydrazine hydrate. The reaction is carried out in a protic solvent, preferably ethanol, at about reflux, preferably about 80xc2x0 C., for about 24 hours. When the reaction is substantially complete, the product of formula (6) is isolated by conventional means, for example by partitioning between ether and water, separation of the organic layer, drying the solvent, and removal of solvent under reduced pressure. The compound of Formula (6) is used for the next step without purification.
Step 2xe2x80x94Preparation of Formula I
The compound of formula (6) is converted to a compound of Formula I by reaction with an optionally substituted 1,3-propanedione of formula (7). The reaction is carried out in a protic solvent, preferably methanol/acetic mixture, at about reflux, for about 24 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by removal of solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
The compounds of the present invention can be prepared according to the following last steps:
1. Contacting a compound of the formula 
with an anion formed from a pyrazole of the formula: 
and a strong base, preferably sodium hydride.
2. Contacting a compound of Formula I in which R2 is hydrogen: 
with an acid halide of the formula RC(O)Hal, where RC(O)xe2x80x94 represents R2 when R2 is acyl, Hal is halogen, preferably chloro, in the presence of a base, preferably a tertiary amine.
3. Contacting a compound of formula (6): 
with an optionally substituted propanedione of the formula: 
General Utility
The compounds of Formula I are effective in the treatment of conditions that respond to administration of A2B adenosine receptor antagonists. Such conditions include, but are not limited to, diarrhea, atherosclerosis, restenosis, diabetic retinopathy, cancer, senile dementia, Alzheimer""s disease, Parkinson""s disease, traumatic brain injury, and Type I hypersensitivity reactions, including asthma, atopic eczema, and hay fever.
Testing
Activity testing is conducted as described in those patents and patent applications referenced above, and in the Examples below, and by methods apparent to one skilled in the art.
Pharmaceutical Compositions
The compounds of Formula I are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The compounds of Formula I may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington""s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and xe2x80x9cModern Pharmaceuticsxe2x80x9d, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).
Administration
The compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
One mode for administration is parental, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of Formula I in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral administration is another route for administration of the compounds of Formula I. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound of Formula I, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
The compositions are preferably formulated in a unit dosage form. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds of Formula I are effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 10 mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of a compound of Formula I, more preferably about 50-200 mg. It will be understood, however, that the amount of the compound of Formula I actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.